This invention relates to a novel and useful drug delivery device for releasing drug at a controlled rate for a prolonged period of time to produce a local or systemic physiological or pharmacological effect. The drug delivery device is comprised of a reservoir surrounded by a wall. The reservoir is comprised of a drug within a solid carrier permeable to the passage of the drug and in which the drug has limited solubility. The wall of the device is comprised in at least a part of a microporous material, the pores of which contain a drug release rate controlling medium permeable to the passage of the drug. Both the solid drug carrier and the medium present in the pores of the microporous wall are permeable to the passage of drug, as by diffusion, but the permeability of the medium to the drug is lower than the permeability of the solid carrier to the drug. Accordingly, drug released through the medium in the pores of the wall is the drug release rate controlling step for releasing drug from the drug delivery device of the invention.
The terms and phrases such as "reservoir", "carrier", "drug", "limited solubility", "medium", and the like that appear throughout the specification and the accompanying claims are defined in the specification in the section entitled, "Detailed Description of the Invention."
In many therapeutic programs pertaining to the management of health and disease, it is desirable and indicated to use a drug delivery device to provide for the slow release of a drug to the body at a controlled rate over a prolonged period of time to achieve a desired physiologic or pharmacologic effect. In many instances, such a rate of release of the drug from a drug delivery device should have a zero order time dependence, that is, the rate of drug release is independent of time.
Different approaches have been tried by the prior art to obtain such a drug delivery device. One approach, which has received great attention, is to mix a drug with a carrier material that is gradually broken down by body fluids with the drug released as the carrier disintegrates. Numerous carriers have been used in such devices including waxes, oils, fats, soluble polymers, and the like. While some of these devices have provided for a delayed release of the drug, the desired constant release rate for a prolonged period has not been obtained. One reason for this is that as the carrier disintegrates the surface area of the dosage unit decreases, concomitantly exposing increasingly smaller quantities of the carrier to the surrounding body fluids. This inherently results in a decline in the release rate over time.
Another approach to this problem has been to disperse the drug throughout a solid matrix material through which the desired amount of the drug is released by diffusion. But, this type of drug delivery device has proven incapable of providing a zero order drug release rate, because of the drawback that the release rate (dM.sub.t /dt) instead of being zero order (dM.sub.t /dt = constant) decreases with time (dM.sub.t /dt = constant x t.sup.-.sup.1/2) during much of the drug release history; J. Pharm. Sci., Vol. 52, pages 1145 to 1149, 1963.
Still another approach has been to enclose the drug within a single capsule having a polymeric wall or walls through which the drug can pass, for example, by diffusion. An approach of this kind is set forth in U.S. Pat. No. 3,279,996. These devices too, have inherent difficulties. One difficulty encountered is that small devices containing a small amount of dry, powdered drug are hard to fabricate because the device can be manufactured from only a few, critical materials and further because these selected materials containing the drug must be non-toxic as they contact the body. Additionally, these prior art devices have generally been based on the use of a single material, such as silicone rubber polymers, especially polydimethylsiloxane, as the diffusion control membrane. In large part, these polymers were selected because of their permeability to some important drug molecules. But, it has been found that mere high permeability without consideration of release rate controlling properties can be a significant disadvantage which defeats the primary object of an acceptable drug delivery device. Thus, with many important drug molecules, such as progesterone, the diffusion rate through a polydimethylsiloxane membrane is very great, and it is often greater than the rate of clearance of the diffused drug from the outer surface of the capsule. In many instances this results in the rate limiting step being clearance of the drug from the exterior of the capsule, rather than diffusion through the capsule wall. Clearance rate within the body is difficult to control, as it is subject to frequent change, and this inherently defeats the objects of providing a drug delivery device which releases drug at a constant rate over prolonged time.
In my copending application, U.S. Ser. No. 42,786 filed June 2, 1970 and now U.S. Pat. No. 3,854,480, and assigned to the assignee of this invention, there is described a novel drug delivery device comprised of a drug dispersed in a solid matrix permeable to passage of the drug and surrounded by a membrane, also permeable to passage of the drug but at a lower rate than through the matrix. That device has proven itself capable of zero order drug release and represents a substantial improvement over previously proposed drug delivery devices. The drug release rate in these devices is controlled by using nonporous wall forming materials for releasing the drug, and the release rate for the drug is proportional to its diffusion coefficient in the wall and to the solubility of the drug in the wall. In making these drug delivery devices available to the art, these parameters are developed for each drug, and it has now been found that this can require a large number of wall forming materials for different drugs. This often adds considerable complexity to the design of drug delivery devices.
It is also known to the art to incorporate drug into certain types of liquid carriers, usually in microcapsule formulations, for example, as in U.S. Pat. No. 3,464,413. However, these microcapsules are not designed for the controlled release of drug for a prolonged period of time by using drug release rate controlling materials. The microcapsules are frequently crushable, and they merely function as drug carriers supplying their drug in bulk, and not in controlled amounts by rupture of the microcapsules. Therefore, these types of capsules are not suitable for releasing drug at a controlled rate for a prolonged period of time. One additional approach used is described in Die Pharmaz. Ind, Vol. 51, No. 6, pages 409 to 412, 1969. This approach consists of coating a drug with a coat that undergoes a loss of mechanical properties in the environment of use such as swelling to form random holes for release of drug therethrough over a certain concentration range. This procedure has limited use because it requires a different coat for each environmental pH and the release of drug is dependent on its solubility in the fluid of the environment. These limitations inherently prevent these devices from reaching practical application.